EP0400916A2 - 4,5,6,11-Tetrahydrobenzo[6,7]-cycloocta[1,2-b]thiophen-6,11-imine und 6,11-Dihydrobenzo[6,7]-cycloocta[1,2-b]thiophen-6,11-imine - Google Patents

4,5,6,11-Tetrahydrobenzo[6,7]-cycloocta[1,2-b]thiophen-6,11-imine und 6,11-Dihydrobenzo[6,7]-cycloocta[1,2-b]thiophen-6,11-imine Download PDF

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Publication number
EP0400916A2
EP0400916A2 EP90305716A EP90305716A EP0400916A2 EP 0400916 A2 EP0400916 A2 EP 0400916A2 EP 90305716 A EP90305716 A EP 90305716A EP 90305716 A EP90305716 A EP 90305716A EP 0400916 A2 EP0400916 A2 EP 0400916A2
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solution
mmol
mixture
ether
concentrated
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French (fr)
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EP0400916B1 (de
EP0400916A3 (de
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Ralph P. Robinson
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Pfizer Inc
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Pfizer Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/18—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • United States Patent No. 4,414,154 refers to compounds of the fornula The compounds are said to be useful as anticonvulsants, anxiolytics and antidepressants.
  • the foregoing compounds do not have a thiophene ring as part of the tricyclic ring system.
  • United States Patent No. 4,252,810 refers to compounds of the formula The compounds are said to be useful as antianxiety agents and as muscle relaxants.
  • the compounds of the '810 patent have a different orientation of the thiophene ring than the compounds of the present invention as well as a cyclohepta- rather than a cycloocta-ring as part of the bridged tricyclic ring system.
  • the present invention relates to compounds of the formula wherein the broken line represents an optional bond, R1 and R4 are independently selected from hydrogen and C1 to C6 alkyl, and R2 and R3 are independently selected from hydrogen, C1 to C6 alkyl, halogen (e.g., fluoro, chloro, bromo and iodo), C1 to C6 alkoxy and C1 to C6 alkylthio, and pharmaceutically acceptable salts thereof.
  • halogen e.g., fluoro, chloro, bromo and iodo
  • Preferred compounds are compounds of the Formula I wherein R1 equals hydrogen. More preferably, R1 equals hydrogen and R4 equals methyl.
  • Specific preferred compounds of the present invention are the following: 11-methyl-4,5,6,11-tetrahydrobenzo[6,7]cycloocta­[1,2-b]thiophen-6,11-imine; 8-fluoro-11-methyl-4,5,6,11-tetrahydrobenzo[6,7]­cycloocta[1,2-b]thiophen-6,11-imine; and 8,11-dimethyl-4,5,6,11-tetrahydrobenzo[6,7]­cycloocta[1,2-b]thiophen-6,11-imine.
  • the (+) isomer of 11-methyl-4,5,6,11-tetra­hydrobenzo[6,7]cycloocta[1,2,-b]thiophen-6,11-imine is particularly preferred.
  • the present invention also relates to a pharmaceutical composition for the treatment of cerebral ischemia, Alzheimer's disease or convulsions comprising an amount of a compound of the formula I or a pharmaceutically acceptable salt thereof that is effective in preventing neuronal damage following cerebral ischemia or during the progression of Alzheimer's disease or in preventing convulsions, and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for the treatment of cerebral ischemia, Alzheimer's disease or convulsions comprising an amount of a compound of the formula I or a pharmaceutically acceptable salt thereof that is effective in preventing neuronal damage following cerebral ischemia or during the progression of Alzheimer's disease or in preventing convulsions, and a pharmaceutically acceptable carrier.
  • Preferred compositions of the present invention contain the foregoing preferred and specific preferred compounds.
  • the present invention also relates to a process for the preparation of formula I and pharmaceutically acceptable salts thereof.
  • the present invention also relates to novel intermediates in the preparation of formula I.
  • Such intermediates are compounds of the formula wherein R4 equals hydrogen or methyl, R3 equals hydrogen, fluorine or methyl and R5 is a protecting group such as CO2CH2CCl3.
  • the compounds of the present invention may be prepared as shown in the reaction scheme set forth below:
  • the first step in the sequence involves dilithiation of the appropriate N-silyl benzenemethanamine derivative of Formula II by treatment of Formula II with at least 2 equivalents of an alkyl lithium reagent, preferably com­mercial n-butyl lithium sold as a solution in hexane.
  • Suitable solvents include anhydrous dialkyl ethers, tetra­hydrofuran, saturated hydrocarbons or any combination thereof.
  • 0.5 to 1.0 equiva­lents of tetramethylethylenediamine may be used as a co-solvent.
  • the lithiation process is generally carried out at temperatures ranging from about 0°C to the boiling point of the solvent being used, although temperatures down to minus 78°C may be used if desired.
  • a period of about 2 hours is generally allowed for complete dilithiation to take place; longer reaction times (e.g., about 12 hours) are acceptable.
  • the resulting dilithio-N-silyl benzenemethan­amine derivative is generally not isolated and can be allowed to react with the appropriate 4,5-dihydro-6H-cyclo­penta[b]thiophen-6-one in the same vessel in which the lithiation is carried out.
  • the 4,5-dihydro-6H-cyclo­penta[b]thiophen-6-one is typically introduced in solution using an anhydrous inert solvent of the type used in the lithiation process. This step is carried out at external bath temperatures ranging from about minus 100°C to about 0°C although minus 78°C is the preferred temperature.
  • the ensuing reaction is allowed to take place over a period of about 0.5 to about 3 hours. At this point, the reaction mixture is quenched with an excess of saturated NH4Cl solution and allowed to equilibrate to room temperature. Following dilution with H2O, the mixture is typically extracted twice with diethyl ether. The combined diethyl ether extracts are then concentrated under reduced pressure to remove the solvents.
  • the oily residue is taken up in a mixture of dilute mineral acid and an inert miscible solvent, preferably tetrahydrofuran, and allowed to stir at room temperature over a period of about 2 to about 24 hours; longer times are acceptable. Removal of most of the co-solvent is then carried out under reduced pressure. The remaining residue is diluted with H2O and is extracted with diethyl ether and the extracts are discarded. By addition of base (typically NaOH, KOH and/or NaHCO3), the pH of the aqueous layer is adjusted to at least 9. The mixture is again extracted twice with ether and the combined extracts are dried over solid Na2SO4 or K2CO3. After filtration, the solvent is evaporated under reduced pressure.
  • base typically NaOH, KOH and/or NaHCO3
  • the residue is typically placed under high vacuum to remove traces of solvent and to remove benezenemethanamine or derivatives thereof. Isolation of the desired compound of Formula III can then be achieved by chromatography on silica gel, generally using a combination of methanol and chloroform as eluant.
  • the next step of the sequence involves acylation of the appropriate compound of Formula III with 2,2,2-trichloroethylchloroformate and subsequent acid catalyzed rearrangement to the corresponding compound of Formula VI.
  • the compound of Formula III is generally treated with about 1 to about 1.5 equivalents of 2,2,2-trichloroethylchloro­formate in the presence of 1 to 2 equivalents of a tertiary amine, a pyridine or other base soluble in the solvent being used which will not react with 2,2,2-trichloroethyl­ chloroformate.
  • the preferred solvent is dichloromethane, although other solvents, such as chloroform, carbon tetra­chloride, benzene, and other aprotic solvents are also suitable.
  • the reaction is generally carried out at 0°C, although temperature as high as the boiling point of the solvent or as low as minus 78°C can be used. Reaction times ranging from about 5 minutes to several hours may be employed when running the reaction at 0°C.
  • the inter­mediate N-2,2,2-trichloroethyloxycarbonyl derivative compound of Formula IV need not be isolated when the acylation reaction is run in solvents such as dichloro­methane or other halogenated hydrocarbons.
  • the reaction mixture is treated directly with HBr gas which is bubbled through the solution for a period long enough (typically 5 minutes) to achieve complete saturation of the reaction mixture.
  • the preferred temperature for this step is about 0°C; however other temperatures ranging from minus 78°C to the boiling point of the solvent can be used.
  • the reaction is stirred for a time ranging from about 0.5 hour to several days, typically, reaction time is about 2 hours. At this point, the solvent is removed under reduced pressure.
  • the desired compound of Formula VI can then be isolated by liquid chromatography of the residue on silica gel. A mixture of ethyl acetate and hexane is commonly used as the eluant.
  • the final step in the preparation of compounds of Formula I involves removal of the 2,2,2-trichloro­ethyloxycarbonyl protecting group from the intermediate compound of Formula VI. This can be achieved by the use of standard methods described in the chemical literature.
  • the compound of Formula VI is dissolved in acetic acid and treated with an excess of zinc powder.
  • the reaction is usually run at about 50°C although temperatures between the freezing and boiling points of acetic acid may be used. When run at 50°C reaction times between about 1 and about 24 hours are commonly used.
  • the unreacted zinc is removed by filtration and most of the acetic acid is removed by evaporation under reduced pressure.
  • the residue is taken up in diethyl ether or methyene chloride and washed with NaHCO3 solution, water and brine.
  • the solution is dried (Na2SO4, K2CO3, or MgSO4), filtered and evaporated to provide the crude compound of Formula I. Purification is commonly achieved by the use of liquid chromatography on silica gel.
  • the compounds of formula I are often oils but can be converted to crystalline salts by standard methods.
  • the compounds of formula I and their pharmaceutically acceptable salts are effective excitatory amino acid receptor antagonists and are thus useful as agents for the prevention of neuronal damage in the brain.
  • the compounds are useful for the prevention of neuronal damage following cerebral ischemia and during the pro­gression of Alzheimer's disease.
  • the compounds function as anticonvulsants.
  • the compounds of the formula I and their pharmaceuti­cally acceptable salts may be administered to a subject in need of treatment by a variety of conventional routes of administration, including oral, topical, rectal, parenteral and by inhalation in aerosol form.
  • these compounds will be administered orally or parenterally at dosages between about 0.01 to about 50 mg/kg of body weight weight of the subject to be treated per day, preferably from about 0.05 to about 10 mg/kg.
  • some variation in dosage will necessarily occur depending on the condition of the subject being treated and the activity of the compound being employed.
  • the person responsible for administration will, in any event, determine the appro­priate dose for the individual subject.
  • the compounds of the formula I and their pharmaceuti­cally acceptable salts may be administered alone or in combination with pharmaceutically acceptable carriers, in either single or multiple doses.
  • suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.
  • the pharmaceutical compositions formed by combining the novel compounds of formula I and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, injectable solutions and the like.
  • These pharmaceutical compositions can, if desired, contain additional ingre­dients such as flavorings, binders, excipients and the like.
  • tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate may be employed along with various disintegrants such as starch, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • various disintegrants such as starch, alginic acid and certain complex silicates
  • binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • sodium lauryl sulfate and talc are often useful for tabletting purposes.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules. Preferred materials for this include lactose or milk sugar and high molecular weight polyethylene glycols.
  • the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and combinations thereof.
  • a solution of a com­pound of the formula I or a pharmaceutically acceptable salt thereof in sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solution may be employed.
  • aqueous solutions should be suitably buffered, if necessary, and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
  • the activity of the compounds of the formula I as agents for the prevention of neuronal damage in the brain and as anticonvulsants may be determined by a number of standard biological or pharmacological tests. Suitable tests include in vivo tests (such as the prevention of audiogenic seizure in DBA/2 mice and prevention of NMDA-­induced seizures in CF-1 mice) as well as in vitro tests (such as displacement of 3H-TCP from brain slices and inhibition of NMDA-induced cyclic-GMP).
  • a sample of the hydrobromide salt was prepared by addition of a solution of HBr in ether to an ice cold solution of the amine in ether. The precipitate was recrystallized from a mixture of ether and methanol; m.p. greater than 250°C. Analysis calculated for C15H16BrNS: C, 55.90; H, 5.00; N, 4.35. Found: C, 55.79; H, 5.02; N, 4.38.
  • the crude oily product was then subjected to flash chromatography on two successive silica gel columns.
  • the first column utilized 14% EtOAc/hexanes as eluant and served to remove unreacted DBU from the mixture.
  • the second column was carefully run using 5% EtOAc/hexanes as eluant and successfully separated the two major products of the reaction.
  • the less polar product (144 mg, 21%) was identified as 11-methyl-6,11-dihydrobenzo[6,7]cycloocta­[1,2-b]thiophene-6,11-imine-12-carboxylic acid-2,2,2-tri­chloro ethyl carbamate and was set aside.
  • the hydrobromide salt was prepared by addition of a solution of HBr in ether to a solution of the amine in ether at 0°C and recrystallized from MeOH/ether; m.p. 287-289°C. MS : m/z (relative percent) 239 (100), 224 (28), 212 (44), 197 (41). Exact mass calculated for C15H13NS: 239.0769. Found: 239.0728. Analysis calculated for C15H14BrNS: C, 56.26; H, 4.41; N, 4.37. Found: C, 55.91; H, 4.35; N, 4.38.
  • the hydrochloride salt was prepared in a mixture of isopropanol/ether (37 mg); m.p. greater than 240°C. MS : m/z (relative percent) 255 (100), 240 (88), 158 (82).
  • the 1H NMR spectrum of this material showed it to consist of a mixture (about 1:1) of 8-fluoro-11-methyl-4,5,6,11-­tetrahydrobenzo[6,7]cycloocta[1,2-b]thiophen-6,11-imine-­ 1,2-carboxylic-2,2,2-trichloroethyl ester and 6′-fluoro-­4,5,2′,3′-tetrahydro-spiro[6H-cyclopenta[b]thiophene-­6,1′-[1H]isoindole]-2′-carboxylic acid-2,2,2-trichloro­ethyl ester (the major components of the reaction).
  • the oily mixture (460 mg, 51%) was thus dissolved in glacial acetic acid (50 ml) and treated with zinc powder (653 mg, 10 mmol) to effect removal of the 2,2,2-trichloroethyloxycarbonyl group.
  • the mixture was stirred under nitrogen in an oil bath at 60°C for overnight and then cooled to room temperature. Excess zinc was removed by filtration through diatomaceous earth [Celite (trademark)] (washing with CH2Cl2) and the solvents were evaporated in vacuo .
  • the oily residue was dissolved in CH2Cl2 and washed with saturated NaHCO3 solution and brine. The solution was dried (MgSO4) and concentrated in vacuo .
  • Diastereomer A (113 mg, 0.26 mmol) was dissolved in a mixture of p-dioxane (30 mL) and water (10 mL). After addition of 1N NaOH solution (2.32 mL, 2.32 mmol), the mixture was heated at reflux for 6 days and then cooled. The solvents were removed in vacuo to leave a residue which was subjected to flash chromatography on silica gel using ethyl acetate as eluant.
  • Diastereomer B (94 mg, 0.215 mmol) was dissolved in a mixture of p-dioxane (23 mL) and water (8 mL). After addition of 1N NaOH solution (1.93 mL, 1.93 mmol), the mixture was heated at reflux for 6 days, and then cooled. The solvents were removed in vacuo to leave a residue which was subjected to flash chromatography on silica gel using ethyl acetate as eluant.
  • (+)- and (-) enantiomers each displayed 1H NMR spectra identical to the racemic material and were sepa­rately converted to their respective hydrochloride salts as described in Example 9.
  • the (+)-enantiomer was found to be approximately eight times as active as the (-)-enantiomer when tested in the 3H-TCP binding assay.
  • P2 membranes from rat forebrain were suspended in 5mM tris(hydroxymethyl)aminomethane hydrochloride buffer (pH 7.4). A solution of the test compound in H2O or DMSO/H2O was added followed by a solution of 3H-TCP. The mixture was incubated for 20 minutes at 30°C and then injected onto a glass fiber filter. The filters were washed with cold buffer and placed in vials for subsequent liquid scintilla­tion spectrometry. IC50 were calculated from the amount of tritium label retained on the filters.
  • the title compounds of Examples 9, 22 and 26 were tested in this 3H-TCP binding assay and were found to display an IC50 of no greater than 40 nanomolar. In this assay, the title compounds of Examples 4, 14, 15 (free amine), 16 and 18 were found to display an IC50 of no greater than 2 micromolar.

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EP90305716A 1989-06-01 1990-05-25 4,5,6,11-Tetrahydrobenzo[6,7]-cycloocta[1,2-b]thiophen-6,11-imine und 6,11-Dihydrobenzo[6,7]-cycloocta[1,2-b]thiophen-6,11-imine Expired - Lifetime EP0400916B1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PCT/US1989/002387 WO1990015060A1 (en) 1989-06-01 1989-06-01 4,5,6,11-TETRAHYDROBENZO[6,7]CYCLOOCTA[1,2-b]THIOPHEN-6,11-IMINES AND 6,11-DIHYDROBENZO[6,7]CYCLOOCTA[1,2-b]THIOPHEN-6,11-IMINES
WOPCT/US89/02387 1989-06-01

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EP0400916A2 true EP0400916A2 (de) 1990-12-05
EP0400916A3 EP0400916A3 (de) 1991-11-27
EP0400916B1 EP0400916B1 (de) 1994-11-09

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EP90305716A Expired - Lifetime EP0400916B1 (de) 1989-06-01 1990-05-25 4,5,6,11-Tetrahydrobenzo[6,7]-cycloocta[1,2-b]thiophen-6,11-imine und 6,11-Dihydrobenzo[6,7]-cycloocta[1,2-b]thiophen-6,11-imine

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EP (1) EP0400916B1 (de)
JP (1) JPH0662630B2 (de)
AT (1) ATE113950T1 (de)
CA (1) CA2017911A1 (de)
DE (1) DE69013983T2 (de)
DK (1) DK0400916T3 (de)
ES (1) ES2063266T3 (de)
FI (1) FI98462C (de)
IE (1) IE64909B1 (de)
PT (1) PT94205B (de)
WO (1) WO1990015060A1 (de)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0441598A2 (de) * 1990-02-08 1991-08-14 Zeneca Inc. Spiroisoindole Verbindungen
US5196415A (en) * 1989-05-09 1993-03-23 The United States Of America As Represented By The Department Of Health And Human Services 5-aminocarbonyl-5H-dibenzo[a.d]cyclohepten-5,10-imines for treatment of epilepsy and cocaine addiction
US6960289B2 (en) 1996-06-19 2005-11-01 Lifescan, Inc. Electrochemical cell

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5260309A (en) * 1989-06-01 1993-11-09 Pfizer Inc. 4,5,6,11-tetrahydrobenzo [6,7] cycloocta [1,2-b]thiophen-6,11-imines and 6,11-dihydrobenzo [6,7] cycloocta [1,2-b] thiophen-6,11-imines

Citations (2)

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EP0011206A1 (de) * 1978-11-15 1980-05-28 Merck & Co. Inc. 9,10-Dihydro-4H-benzo(4,5)cyclohepta(1,2-b)thiophen-4,9-imine, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Präparate
US4329465A (en) * 1977-09-19 1982-05-11 Merck & Co., Inc. Dibenzo[a,d]cycloocten-6,12-imines

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US3816455A (en) * 1971-04-23 1974-06-11 Mcneilab Inc Certain benzothiepino-indoles and indoline-thiochromans
US4112110A (en) * 1974-02-22 1978-09-05 Ciba-Geigy Corporation Oxygenated azatetracyclic compounds
US4414154A (en) * 1977-09-19 1983-11-08 Merck & Co. Inc. Dibenzo[a,d]cycloocten-5,12-imines

Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
US4329465A (en) * 1977-09-19 1982-05-11 Merck & Co., Inc. Dibenzo[a,d]cycloocten-6,12-imines
EP0011206A1 (de) * 1978-11-15 1980-05-28 Merck & Co. Inc. 9,10-Dihydro-4H-benzo(4,5)cyclohepta(1,2-b)thiophen-4,9-imine, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Präparate

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
TETRAHEDRON LETTERS, vol. 30, no. 39, September 1989, pages 5203-5206, Oxford, GB; R.P. ROBINSON et al.: "A novel rearrangement forming 4,5,6,11-tetrahydrobenzo[6,7Ücycloocta[1,2-bÜthiophen-6,11-imines" *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5196415A (en) * 1989-05-09 1993-03-23 The United States Of America As Represented By The Department Of Health And Human Services 5-aminocarbonyl-5H-dibenzo[a.d]cyclohepten-5,10-imines for treatment of epilepsy and cocaine addiction
EP0441598A2 (de) * 1990-02-08 1991-08-14 Zeneca Inc. Spiroisoindole Verbindungen
EP0441598A3 (en) * 1990-02-08 1992-03-11 Ici Americas Inc. Spiroisoindole compounds
US6960289B2 (en) 1996-06-19 2005-11-01 Lifescan, Inc. Electrochemical cell

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FI915646A0 (fi) 1991-11-29
WO1990015060A1 (en) 1990-12-13
CA2017911A1 (en) 1990-12-01
PT94205A (pt) 1991-02-08
EP0400916B1 (de) 1994-11-09
IE901951L (en) 1990-12-01
JPH0320278A (ja) 1991-01-29
ES2063266T3 (es) 1995-01-01
PT94205B (pt) 1997-01-31
DE69013983T2 (de) 1995-03-16
FI98462C (fi) 1997-06-25
DK0400916T3 (da) 1994-12-05
JPH0662630B2 (ja) 1994-08-17
IE64909B1 (en) 1995-09-20
ATE113950T1 (de) 1994-11-15
EP0400916A3 (de) 1991-11-27
FI98462B (fi) 1997-03-14
DE69013983D1 (de) 1994-12-15

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